DK142618B - Process for the preparation of 2-aminomethyl-1-ethylpyrrolidine. - Google Patents

Description

<11) EMPLOYMENT WRITING 142618 f ^ Éw) \ Ra / DENMARK <51), nt'C '· 3 c 25 B 2 ° 3 / o! '(21) Application No 36IO / 76 (22) Filed on 10 August. 1976 (24) Race day 10. SUg · 197 6

(44) The application submitted and Q

the petition published on I · ueC. 1 you DIRECTORATE FOR.

PATENT AND TRADEMARKS <30> Requested from 11 August. 1975a £ 7295/75 * J? (71) YAMANOUCHI PHARMACEUTICAL CO. LTD., 5-1, Nihonbashi-Honcho 2-chome, "Chuo-ku, Tokyo, JP.

(72) Inventor: Keijiro Odo, 15, Hlroo 3-chome, Shlhuya-ku, Tokyo, JP: Eiichi Ichikawa, 887, Shimoda-machi, Kohoku-ku, Yokohama-shl, Kanagawa, JP: Ka = zuharu Taraazawa, 1013 -2, Oazakaminoda, Shiyaoka-machi, minaxal ^ ealtamar gun, SaTtama, JP: Kozo Takahashi, 837s Nishicoizumi-cho, Nerima-ku, To = kyo, JP.

(74) Plenipotentiary in the proceedings:

Hof man-Bang & Bout engineering firm. (54) Process for preparing 2-aminomethyl-1-ethylpyrrolidine.

The invention relates to a particular process for the preparation of 2-aminomethyl-1-ethylpyrrolidine (II) by reduction of 1-ethyl-2-nitromethylene pyrrolidine (I), which is characterized in that the reduction is carried out electrolytically under neutral to slightly basic conditions. using copper 4 * 'i! as a cathode.

2-Aminomethyl-1-ethylpyrrolidine (II) is a known compound useful as an intermediate in the synthesis of various drugs, such as N- (1-ethylpyrrolidin-2-ylmethyl) -6-chloro-5- (ethylamino-3) -methoxypyrazine-2-carboxamide (Danish patent no.

139,846) and 5- (aminosulfonyl) -N - [(1-ethyl-2-pyrrolidinyl) methyl) -2-methoxybenzamide is fine. surname: sulpiride, Merck Index ninth ed.).

2 142618

A process for reducing the starting material (i) with hydrogen is known in the presence of a metallic hydrogenation catalyst or with an acid and a metal, and in practice the process of catalytic reduction with hydrogen is carried out in the presence of a Raney nickel catalyst (U.S. Pat.

3,748,341 and GB Patent No. 1,374,818).

However, the process of catalytic reduction is insufficient for industrial practice as the process requires a large amount of expensive Raney nickel catalyst and the yield is 65-81.7 #.

It has now been found according to the invention that the desired compound (II) can be obtained by electrolytic reduction of the starting material. (I) Under neutral to slightly basic conditions using copper as a cathode in an industrially advantageous manner in a very pure state and in a yield of over 90%.

The electrolytic reduction of the process according to the invention is a cathodic reaction and can be illustrated by the following reaction scheme: CH2CH3 + 8εθ + 8H ^ CH2CH3 + 2H2 ° (X) (II)

In the process of the invention, as mentioned, the compound (II) can be obtained in a very pure state and in yields of more than 90%, and the materials used in the reaction are 8e electrons and protons. Therefore, the process according to the invention is industrially advantageous compared to the known catalytic reduction, using a large amount of expensive Raney nickel catalyst. Furthermore, the process of the invention is also industrially advantageous in that it is unnecessary to remove unreacted reducing agent, catalyst or conversion products thereof from the reaction mixture and that the reaction does not require difficult conditions such as high temperature, high pressure, etc.

3 142618

Admittedly, it is known that a 2-aminoethyl compound of the saturated alkyl amines, like the desired product (II), can be prepared by electrolytically reducing a β-nitrostyrene belonging to the α-nitroalkenes as well as the starting material (I) under acidic conditions using mercury. or lead as cathode (Kirk-Othmer, "Encyclopedia of Chemical Technology",

Vol. 5, 664 (i960)). However, it has unexpectedly been found that the desired result in the process of the invention is not achieved when the electrolytic reduction is carried out under the above acidic conditions, but only when the electrolytic reduction is carried out under neutral to slightly basic conditions using copper as the cathode.

In the following, a number of results obtained by electrolytic reduction of 1-ethyl-2-nitromethylene pyrrolidine (I) are reported under various conditions.

Trial Procedure i

The experiment was performed using an H-type electrolysis apparatus with a sintered glass diaphragm or a B type electrolysis apparatus with a porous unglazed cylinder in the center as the diaphragm.

A cathode and a catholyte solution were placed in the cathode chamber of the apparatus and a platinum disc (30 mm in diameter) as anode and an anolyte solution was placed in the anode chamber. After prelectrolysis for 10 minutes, the starting material (I), 1-ethyl-2-nitromethylene pyrrolidine, was added to the cathode chamber and a controlled current of 0.8-1.0 A was applied until a theoretical or slightly excess amount of electricity was consumed. . Then, the amount of compound (II), 2-aminomethyl-1-ethylpyrrolidine formed, was determined from the thin layer chromatogram of the reaction product. The result is given in Table 1.

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As is clear from the results in the table, the desired compound (II) was hardly formed in Experiments Nos. 1-4 using acidic electrolyte solutions; and in Experiment No. 5-15 using basic electrolyte solutions, the desired compound (II) was obtained only in Experiment No. 14 ag 15 using copper as the cathode.

Thus, the process of the invention is carried out by electrolytically reducing the starting material (I) under neutral to slightly basic conditions using copper As cathode. Since the electrolytic reduction is a cathodic reaction, it is practically accomplished by adding the starting material (I) to a neutral to slightly alkaline aqueous electrolyte solution array in a cathode chamber of an electrolysis apparatus and reviewing the theoretical or a slight excess amount of electricity. In this case, it is preferred that an organic solvent be added to the cathode chamber, since the starting material (I) is insoluble in water and the starting material (i) can be added to the cathode chamber in the form of an organic solution. The organic solvent used for this purpose must be an inert organic solvent which is miscible with water and dissolves the starting material (!). An example of a suitable solvent may be mentioned an alcohol such as methanol and ethanol.

Advantageously, the electrolytic reduction in the process of the invention is carried out using an electrolytic apparatus divided into a cathode chamber and an anode chamber of a porous diaphragm such as a porous unglazed diaphragm (porous unglazed cylinder, etc.), a porous glass plate (sintered glass diaphragm, etc.). , an ion exchange membrane, membrane filter, etc.

The cathode material for use in the process of the invention is copper and the copper may include copper alloys such as brass (copper-zinc alloy). There is no particular restriction on the shape of the cathode. Eg. For example, a plate, a net, a perforated plate can be used, etc. Furthermore, all insoluble electrodes can be used as the anode material in the method according to the invention. Eg. platinum, palladium, etc. can be used, and there is no particular restriction as to the shape of the anode.

6 142618

The aqueous electrolyte solution used in the process of the invention is neutral to slightly alkaline (pH values from about 7 to about 11). Examples of such aqueous electrolyte solutions are an aqueous ammonium sulfate solution, an aqueous solution of ammonium sulfate and ammonium hydroxide, an aqueous sodium acetate solution, an aqueous sodium carbonate solution, and an aqueous sodium hydrogen carbonate solution. In this case, it is preferred to maintain the property of the aqueous electrolyte solution constant throughout the electrolytic reduction, and if e.g. Therefore, if an aqueous sodium bicarbonate solution or an aqueous sodium carbonate solution is used, it is preferred to carry out the electrolytic reduction while passing carbon dioxide through the electrolyte solution.

There is no particular limitation on the reaction temperature, and e.g. For example, the electrolytic reduction can be carried out at 0-100 ° C, but very high temperatures must be avoided to prevent degradation of the starting material (i) and the resulting product (II) as well as the occurrence of undesirable side reactions. The electrolytic reduction in the process of the invention is usually carried out at room temperature.

The reaction time depends on the concentration of the starting material (i), the nature and concentration of the electrolyte, the current, etc., but the end point of the reaction is usually the point at which the starting material (I) is consumed. Eg. For example, the endpoint of the reaction can be found by checking the disappearance of the starting material (I) by thin layer chromatography as time passes.

Electrolysis is performed by passing the theoretical or excess amount of electricity through the electrolyte solution. In addition, it is preferred to perform a so-called pre-electrolysis prior to the reaction to prevent the occurrence of unexpected difficulties.

The resulting product (II) can be recovered in high purity by purifying the reaction mixture by ordinary chemical operation such as distillation under reduced pressure.

7 142618

The process according to the invention is illustrated in more detail by the following embodiments.

EXAMPLE 1

A 200 ml beaker containing a porous unglazed cylinder (40 mm diameter x 140 mm length) was used as an electrolysis apparatus and a copper plate (40 x 180 mm) was used as a cathode and a platinum disc (30 mm diameter) as anode. 50 ml of a saturated aqueous sodium carbonate solution was introduced into the anode chamber (porous unglazed cylinder) and 70 ml of a 2N aqueous sodium carbonate solution and 30 ml of methanol were introduced into the cathode compartment (beaker). After performing multi-nut pre-electrolysis while passing carbon dioxide through the catholyte solution, 1.56 g of powder of 1-ethyl-2-nitromethylene pyrrolidine was introduced into the cathode chamber and a current of 1 ampere was sent for 2.5 hours. stirring at 20-25 ° C while passing carbon dioxide through the catholyte solution. After the electrolysis was complete, the catholyte solution was acidified and diluted. hydrochloric acid, and the methanol is then distilled off under reduced pressure. The residue formed was made strongly basic with a dilute aqueous sodium hydroxide solution and the resulting solution was extracted with ether. The ether extract thus formed was dried over anhydrous magnesium sulfate, the ether distilled off, and the residue was subjected to reduced pressure to obtain 1.22 g of oily 2-aminomethyl-1-ethyl-pyrrolidine in a yield of $ 95. The product could be distilled at a boiling point of 58-60 ° C (16 mm. Hg).

The infrared absorption spectrum of the compound was consistent with. the spectrum of 2-aminomethyl-1-ethylpyrrolidine.

EXAMPLE 2

An H-type glass apparatus, which was split in the middle of an anode chamber and a sinter glass diaphragm cathode chamber, was used as the electrode.

ISLAND

lighting apparatus and a copper plate (30 x 40 mm) was used as the cathode and a platinum disc (30 mm diameter) as the anode. Into the anode chamber were introduced 40 ml of a saturated aqueous ammonium sulfate solution and 10 ml of an aqueous 28 $ ammonium hydroxide solution, and in cathode 8, 14 ml of an aqueous 30% methanol solution saturated with ammonium sulfate was introduced. After several minutes of electrolysis, 0.78 g of powder of 1-ethyl-2-nitromethylene pyrrolidine was introduced into the cathode chamber and a current of 1 ampere was passed through for 2 hours with stirring at 20-25 ° C. Upon completion of electrolysis, by treating the product of Example 1, 0.59 g of oily 2-aminomethyl-1-ethylpyrrolidine was obtained in a 90% yield.

The infrared absorption spectrum of the compound was consistent with that of 2-aminomethyl-1-ethylpyrrolidine.

EXAMPLE 5

A 200 ml beaker containing a porous unglazed cylinder (40 mm diameter x 140 mm length) was used as an electro-light apparatus and a copper plate (40 x 180 mm) was used as a cathode and a palladium plate (30 x 40 mm) as anode. 50 ml of a saturated aqueous sodium carbonate solution was introduced into the anode chamber (porous unglazed cylinder) and 70 ml of a 2N aqueous sodium carbonate solution and 30 ml of methanol were introduced into the cathode compartment (beaker). After conducting prelectrolysis for several minutes while passing carbon dioxide through the catholyte solution, 1.56 g of powder of 1-ethyl-2-nitromethylene pyrrolidine was introduced into the cathode chamber and a current of 1 ampere was sent through for 2.5 hours. while stirring at 20-23 ° C while passing carbon dioxide through the catholyte solution. Upon completion of the electrolysis, by treating the product as in Example 1, 1.22 g of oily 2-aminomethyl-1-ethylpyrrolidine were obtained in a yield of 99%.

The infrared absorption spectrum of the compound was consistent with that of 2-aminomethyl-1-ethylpyrrolidine.

EXAMPLE 4

A 200 ml beaker containing a porous unglazed cylinder (40 mm diameter x 140 mm length) was used as an electro-lighting apparatus and a copper plate (40 x 180 mm) was used. as a cathode and a "Hastelloy" plate (resistant nickel alloy, 30 x 40 mm2) as anode. In anode 9 the chamber (the porous unglazed cylinder) 50 ml of a saturated aqueous sodium carbonate solution was introduced and 70 ml of a 2N aqueous sodium carbonate solution and 30 ml of methanol were introduced into the cathode chamber (beaker). After conducting prelectrolysis for several minutes while passing carbon dioxide through the catholyte solution, 1.56 g of powder of 1-ethyl-2-nitromethylene pyrrolidine was introduced into the cathode chamber and a current of 1 ampere was sent through for 2.5 hours. with stirring at 20-23 ° C while passing carbon dioxide through the catholyte solution. After the electrolysis was complete, the catholyte solution was acidified with dilute sulfuric acid and the methanol distilled off under reduced pressure. The residue formed was made strongly basic with a dilute aqueous sodium hydroxide solution and the resulting solution was extracted with ether. The ether extract was dried over anhydrous potassium carbonate, the ether distilled off, and the residue was subjected to distillation under reduced pressure to give 1.22 g of oily 2-aminomethyl-1-ethyl-pyrrolidine in a yield of $ 95. The product could be distilled at a boiling point of 58-60 ° C (16 mm Hg).

The infrared absorption spectrum of the compound was consistent with that of 2-aminomethyl-1-ethylpyrrolidine.

EXAMPLE 5

An H-type glass apparatus, which was split in the middle in an anode chamber and a sinter glass diaphragm cathode chamber, was used as an electrolytic apparatus, and a copper plate (30 x 40 mm) was used as a cathode and a lead plate (30 x 40 mm). ) as an anode. Into the anode chamber was introduced 40 ml of a saturated aqueous ammonium sulfate solution and 10 ml of an aqueous 28 $ ammonium hydroxide solution, and 50 ml of an aqueous 30 $ methanol solution saturated with ammonium sulfate was introduced into the cathode chamber. After several minutes of electrolysis, 0.78 g of powder of 1-ethyl-2-nitromethylene pyrrolidine was introduced into the cathode chamber and a current of 1 ampere was passed through for 2 hours with stirring at 20-23 ° C, after completion of electrolysis, by treating the product as in Example 1, 0.59 g of oily 2-aminomethyl-1-ethylpyrrolidine was obtained in a yield of $ 90.